Corticotropin-releasing factor (CRF) is a 41-residue hypothalamic peptide which stimulates the secretion and biosynthesis of pituitary ACTH leading to increased adrenal glucocorticoid production. CRF was originally isolated and characterized on the basis of its role in this hypothalamic-pituitary-adrenal axis (HPA) [Vale et al., Science Vol. 213:1394-1397 (1981)]. More recently, however, it has been found to be distributed broadly within the central nervous system (CNS) as well as in extra-neural tissues such as the adrenal glands and testes [Swanson et al., Neuroendocrinology Vol. 36:165-186 (1983); Suda et al., J. Clin. Endocrinol. Metab. Vol. 58:919-924 (1984; Fabbri and Dufau, Endocrinology Vol. 127:1541-1543 (1990)], where it may also act as a paracrine regulator or neurotransmitter.
In addition to its critical role of mediating HPA axis activation, CRF has been shown to modulate behavioral changes that occur during stress response. Many of these behavioral changes have been shown to occur independently of HPA activation in that they are insensitive to dexamethasone treatment and hypophysectomy [Britton et al., Life Sci. Vol. 38:211-216 (1986); Britton et al., Life Sci. Vol. 39:1281-1286 (1986); Berridge and Dunn, Pharm. Bioch. Behav. Vol. 34:517-519 (1989)]. In addition, direct infusion of CRF into the CNS mimics autonomic and behavioral responses to a variety of stressors [Sutton et al., Nature Vol. 297:331-333 (1982); Brown and Fisher, Brain Res. Vol. 280:75-79 (1983); Stephens et al., Peptides Vol. 9:1067-1070 (1988); Butler et al., J. Neurosci. Vol. 10:176-183 (1990)]. Furthermore, peripheral administration of CRF or the CRF antagonist, .alpha.-helical CRF 9-41, failed to effect these changes, thus supporting a central role for CRF in such functions.
Central administration of CRF in rodent animal models produces effects that correlate with a state of anxiety such as a reduction in willingness to investigate unfamiliar surroundings [Sutton et al., supra; Sherman and Kalin, Pharm. Biochem. Behav. Vol. 26:699-703 (1987); Berridge and Dunn, supra; Butler et al., supra], decreased sleep [Sherman and Kalin, supra], enhanced fear responses [Sutton et al., supra; Butler et al., supra), decreased food consumption [Morely and Levine, Life Sci. Vol. 31:1459-1464 (1982)] and suppressed sexual behavior (Sirinathsinghji et al., Nature Vol. 305:232-235 (1983)). These changes are similar to behavioral changes observed upon exposure to acute and chronic stressors, and resemble changes that occur in human affective disorders such as the symptom complex characteristic of major depressive disorder, panic disorder and anorexia nervosa [Kaye et al., J. Clin. Endocrinol. Metab. Vol. 64:203-208 (1987); Gold et al., N. Engl. J. Med. Vol. 319:413-420 (1988); Kathol et al., Psych. Clin. N. Amer. Vol. 22:335-348 (1988); Nemeroff, C. B., Pharmacpsychiat Vol. 21:76-82 (1988)].
Currently, a great deal of interest in CRF has been generated in connection with the pathophysiology of mental illness. For example, CRF hypersecretion has been linked to some individuals diagnosed with major depression [Nemeroff et al., Science Vol. 226:1342-1344 (1984)]. While all studies do not support the suggestion that cerebrospinal fluid CRF levels are altered in this group of individuals, most researchers agree that HPA axis responsivity in these individuals is abnormal. Indeed, a large portion of individuals diagnosed with depression have elevated cortisol levels [Roy-Byrne et al., Am. J. Psychiatry Vol. 143:896-899 (1987); Kling et al., J. Clin. Endocrinol. and Metab. Vol. 72:260-271 (1991)). Moreover, in major depression [Holsboer et al., N. Engl. J. Med. Vol. 311:1127 (1984)] and panic disorder (Roy-Byrne, supra] CRF administration results in a blunted ACTH response, suggesting that the pituitary is properly restrained, presumably by the negative feedback effect of elevated levels of glucocorticoids. In view of these findings, it has been suggested that the hypercortisolism in major depression is due to abnormal CRF secretion within the CNS [Gold et al., Psychiat. Clinics of N. Amer. Vol. 11:327-335 (1988)].
In order to more fully investigate the role of abnormal CRF secretion within the CNS, it would be desirable to have available animal models with which to study the effects of CRF hypersecretion.